In order to utilize modern mass-production technology in the encapsulation of dry powder pharmaceutical and vitamin/mineral supplement formulations it is necessary that such compositions have desirable flow characteristics permitting rapid flow through high speed encapsulators without clumping or aggregation. (Remington's Pharmaceutical Sciences ed. A. Usol Mack Publishing Co., Eaton, Pa., 1980, 1553-1584.) Moreover, dry powder formulations to be encapsulated must exhibit a sufficient degree of compressibility to permit the use of piston-type compressive high speed automatic encapsulators therefor. Good compressibility characteristics are additionally necessary to facilitate the production of relatively high-potency pharmaceutical or vitamin/mineral supplement formulations. Conventionally, the requisite flow and compressibility characteristics are provided in dry powder encapsulatable formulations by the addition of significant proportions, e.g., from about 10 to 85% by weight thereof, of various lubricants such as talc, silica (sand), stearic acid, magnesium stearate or glyceryl monostearate (soaps), Carbowax, and/or other fillers and excipients to impart the necessary physical characteristics thereto.
Dry powder formulations utilized in tableted pharmaceuticals or vitamin/mineral supplements must have flow and compressibility characteristics similar to those required for encapsulated materials. (Remington's Pharmaceutical Sciences). In addition, tablet formulations typically contain one or more binders to insure cohesion of the tableted formulation; such binders include, for example, proteins such as gelatin, water-soluble casein derivatives such as sodium caseinate, water-soluble gums such as gum acacia, tragacanth or the like, or water-soluble cellulose derivatives such as methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, or the like. (Cooper, J., Tableting research and technology, Journal Pharmaceutical Sciences, 61:1511-1555, 1972).
Dry powder encapsulated or tableted formulations incorporating such lubricants, fillers, binders and/or other excipients as described hereinabove are disclosed, for example, in Stoyle et al U.S. Pat. No. 3,293,132; Dines et al U.S. Pat. No. 3,518,345; Cavalli U.S. Pat. No. 3,584,114; and Magid U.S. Pat. No. 3,740,432.
A substantial proportion of the population may exhibit allergic or other acute noxious reactions to various of the lubricants, fillers, binders or other excipients utilized in encapsulated or tableted pharmaceuticals or vitamin/mineral supplements. This is particularly the case in connection with vitamin supplements, particularly those containing the water-soluble vitamin C (ascorbic acid) and B-complex vitamins.
Ingestion of vitamin C and B-complex vitamin supplements may be necessary because of poor dietary habits and various environmental stresses (physical, psychological, and secondary due to infection, trauma, ischemia, radiation, chemical exposure or cigarette or alcohol consumption). It is recognized that the tissue ascorbic acid levels of individuals exposed to many of these stresses are decreased by approximately 50%, increasing susceptibility to free radical pathological reactions, disordered functioning of enzymes which require ascorbic acid as a co-factor (e.g., dopamine beta hydroxylase), abnormal prostaglandin production, or generally altered blood flows through tissue. (Demopoulos, H. B., The free radical pathology and the microcirculation in the major central nervous system disorders, Acta Physiologica Scandinavica, Supplement 492:91-119, 1980; and Demopoulos, H. B., The possible role of free radical reactions in carcinogenesis, Journal of Environmental Pathology and Toxicology 3:273-303, 1980.) The water-soluble vitamins are thus required in increased amounts in stressful situations. Since, however, such materials have only a relatively short life span and are excreted in the urine, if the stress situation continues over a prolonged period, or is repetitive, it may be necessary to consume water-soluble vitamin supplements 3 to 4 times daily, over prolonged or indefinite periods.
In view of the large doses thus consumed, negative reactions to the lubricants, fillers or other excipients in water-soluble vitamin supplements have been widely reported. Thus, side effects noted by many of those on high potency vitamin supplement regimens include headaches, significant gastro-intestinal distress (perhaps due to the combined irritating actions of the insoluble lubricants and fillers such as talc and silica, coupled with the detergent action of other excipients such as the stearate soaps), dizziness, malaise, and a host of allergic reactions. (Rawlins, M. D., Adverse reactions to drugs, British Medical Journal 282:974-976, 1981; Bachmann, E., Biochemical effects of gum arabic, gum tragacanth, methylcellulose, and carboxymethylcellulose-Na in rat heart and liver, Pharmacology 17:39-49, 1978; and Rippere, V., Adverse reactions to drugs, British Medical Journal 282:1401, 1981.
Indeed, some of the noxious reactions appear to have a serious biochemical basis. Bachmann, for example, found that some of the complex carbohydrate excipients can: (1) uncouple oxidative phosphorylation, which will decrease the ability of the cells to produce ATP (adenosinetriphosphate); and (2) inhibit mixed function oxidases in the endoplasmic reticulum which function to detoxify drugs and to otherwise metabolize them. Such impairments, potentially, are serious and may explain several types of adverse reactions to pharmaceutical and vitamin/mineral preparations, including malaise, headaches, and gastrointestinal discomfort.
A number of studies have further shown that the use of water-soluble vitamin supplements in high, repetitive doses provides antioxidant functions which are beyond the usual functions of preventing or treating vitamin deficiency diseases. For example, ascorbic acid may thus prevent free radical lipid peroxidation of membrane phospholipids (Leung, H. W., The cooperative interaction between vitamin E and vitamin C in suppression of peroxidation of membrane phospholipids, Biochimica et Biophysica Acta, 664:266-272, 1981.) Lipid peroxidation by free radical reactions is involved in key steps in carcinogenesis (Demopoulous, H. B., The possible role of free radical reactions in carcinogenesis, Journal of Environmental Pathology and Toxicology 3:273-303, 1980; and Rosen, G. M., Spin trapping of the primary radical involved in the activation of the carcinogen, Molecular Pharmacology, 17:233-238, 1980), as well as in occlusive atherosclerosis in which the synthesis of prostaglandin I.sub.2, a substance which prevents platelet adhesion and aggregation, is blocked (Demopoulos, H. B., The free radical pathology and the microcirculation in the major central nervous system disorders, Acta Physiologica Scandinavica, Supplement 492:91-119, 1980; and Editorial: Prevention of thrombosis, The Lancet, Jan. 15, 1977, p. 127.) Noxious reactions to vitamin preparations which contain allergic or other potentially toxic additives (e.g., binders, fillers, lubricants, and the like) may preclude the use of vitamins at the high doses which are necessary to achieve the antioxidant effects necessary to counteract such peroxidation (see the Rawlins, Bachmann and Rippere papers noted above).
A number of other problems have been particularly noted in connection with conventional dry powder formulations incorporating vitamin C in the form of finely divided, amorphous ascorbic acid, sodium ascorbate or the like. For example, the flow characteristics of such products are impaired because of the recognized hygroscopicity of ascorbic acid (see, for example, Pipher U.S. Pat. No. 2,846,353, column 4, lines 45-54; and the aforesaid Stoyl et al U.S. Pat. No. 3,293,132, column 2, lines 21-27). In addition, it has long been known that ascorbic acid is a reducing agent which, upon oxidation (e.g., during storage at elevated temperatures), is susceptible to discoloration (see, for example, Magid U.S. Pat. No. 3,493,659, column 1, lines 21-23). The reducing characteristics of ascorbic acid are of particular concern in multi-vitamin supplements containing various of the B vitamins which may be reduced thereby. For example, vitamin B.sub.12 may be readily reduced in the presence of ascorbic acid to toxic degradation products, which have anti-vitamin B.sub.12 activity and, in some instances, may cause pernicious anemia. (Beaven, G. H., The reduction of vitamin B-12, Nature 176:1264-1265, 1955; and Herbert, V., Vitamin B-12, American Journal of Clinical Nutrition 3:971-972, 1981.)
It has been necessary to devise specific formulations for vitamin supplements incorporating both ascorbic acid and vitamin B.sub.12, to preclude degradation thereof.
For example, Bouchard et al U.S. Pat. No. 2,830,933 discloses such a formulation in which the vitamin B.sub.12 has been absorbed on a synthetic ion-exchange resin prior to blending with other multi-vitamin and/or mineral ingredients. Vitamin B.sub.12 has also been marketed in a stable form within an external matrix; the use of such forms may, however, reduce the bioavailability of the vitamin.
It is, accordingly, among the objects of the present invention to provide dry powder formulations for use as pharmaceuticals or vitamin and/or mineral supplements, which formulations have improved flow and compressibility characterstics facilitating encapsulation or tableting in state-of-the-art, high speed production equipment. A further object of the invention is to provide such formulations which do not require the presence of large quantities, if any, of conventional lubricants, fillers, binders and/or other excipients and which are not, therefore, subject to the toxic side effects associated with such additives. Yet an additional object is to provide dry powder formulations of the indicated types incorporating ascorbic acid as the principal lubricant and/or binder therein, together with a method for the preparation thereof. These and other objects and advantages of the present invention will be apparent from the following description and the accompanying drawings.